Department of PsychologyState University of New York at BuffaloBuffalo, New York 14260-4110

My name is Michael Bozarth. I am an Associate Professor of Psychology
with the State University of New York at Buffalo. I am here today to express
my views on drug addiction, its underlying biological basis, and the widely
popularized notion that nicotine is an addictive substance. Although I
have not previously expressed my position formally, I welcome this opportunity
to "speak out" on a topic of serious concern for the scientific community--that
topic concerns the hasty conclusions draw from an inadequate empirical
database. I strongly believe the scientific community is responsible for
presenting unadulterated 'facts' so the public and the government can make
informed decisions. The lay public trusts scientists to adequately interpret
their data and to remain unbiased by political or other pressures.

In this brief statement I will develop the argument that research has
failed to substantiate the claim that nicotine is addictive. To the contrary,
it is difficult to document even mildly rewarding effects from nicotine.
Because of time limitations, I will restrict my presentation to a few key
issues. The evidence presented here is exemplary of a much larger series
of arguments that refute the main conclusions drawn from the 1988 Surgeon
General's report. An exhaustive, point-by-point critique of that report
is not possible with the limited time allowed for preparation. My main
objective today is to broaden the debate by discussing key points that
have not received adequate consideration.

By way of background, my main research interest is in the biological
mechanisms of motivation and reward with specific application to drug addiction.
Other interests involve motivational theory, biological psychiatry, and
experimental methods used in psychopharmacology research. I consider myself
a "bench" scientist, with daily involvement in the research activity of
my laboratory. This "hands-on" approach to research provides a sharp perspective
on the empirical data in an age when most senior investigators only 'manage'
the research activities of their laboratories. In addition to conducting
research, my university appointment also involves full-time teaching in
my specialty areas (e.g., motivational theory, drug addiction, psychopharmacology).

The Nature of Addiction

The term addiction generally refers to the situation where drug
procurement and administration appear to govern the individual's behavior,
and where the substance seems to dominate the individual's motivational
hierarchy. Two features that distinguish addiction from other behaviors
are its extreme motivational strength and its motivational toxicity. Motivational
strength refers to how hard the individual will work to obtain the substance,
while motivational toxicity describes the substance's ability to disrupt
the individual's normal motivations. This latter characteristic is particularly
interesting because it may serve as a defining characteristic of addiction.

The individual is normally motivated to engage in a variety of behaviors.
The relative importance of these rewards can be ranked to form a motivational
hierarchy. Some motives will rank high, being extremely influential in
the individual's behavior, while others will rank low, being relatively
unimportant. The relative positions of motives on this hierarchy will vary
from individual-to-individual as do what motives are even included on the
list. Certain motivations are shared by all mammals (e.g., food, water,
sexual behavior), while others appear unique to humans (e.g., career, television
viewing).

Addictive substances have the ability to disrupt this motivational hierarchy.
They do this in two ways. First, they can rapidly displace other motives
in the individual's life, thrusting themselves to the top of the motivational
hierarchy. Second, they can disrupt the ability of other, natural rewards
to motivate behavior. The drug addict characteristically places substance
use as their top priority, while losing interest in life's other rewards
(e.g., food, sex). The intense desire to experience the effects of the
addictive substance combined with the inability of natural rewards to engage
behavior is subjectively experienced as a "loss of control." This perception,
in a sense, is correct: the normal controls on the individual's life have
lost their significance and behavior focuses on procurement and self-administration
of the addictive substance.

Animal Models of Addiction

Several animal models of human substance addiction have been studied.
These models can be divided into physiological effect models and reinforcement
models. Physiological effect models include measures of physical dependence
and withdrawal reactions and also some measures of neurochemical activity.
Identified physiological effects of addictive substances are presumed correlates
of their addictive properties, and research examines the characteristics
of these effects. This approach, however, does not directly validate the
model; many physiological effects of a substance are unrelated to its addictive
properties.

Reinforcement models, on the other hand, directly study the reinforcing
effects of a substance. This experimental method offers the closest model
of human substance addiction. Although there are several methods of studying
substance reinforcement, the intravenous self-administration method enjoys
the most widespread acceptance among behavioral scientists. Most substances
that are addictive in humans are readily self-administered by laboratory
animals. This has led to the use of intravenous self-administration as
a screening technique for potential addiction liability. Substances that
are addictive are potent reinforcers in this behavioral paradigm, and compounds
supporting self-administration may have significant addiction potential.
However, many substances that are not considered addictive also reinforce
behavior. It is important to keep in mind that evidence that a substance
is reinforcing does not constitute proof that it is addictive. Additional
tests must be conducted to form this conclusion.

There are a number of characteristics shared by prototypic addictive
substances such as cocaine and heroin. These substances have been tested
extensively in intravenous self-administration, and the general properties
of their self-administration are easily replicable across different laboratories.
By contrast, these consistent findings from self-administration experiments
with the prototypic addictive substances are not present with nicotine.
I would like to briefly summarize some of the characteristics of prototypic
addictive drug self-administration and compare these effects with those
reported for nicotine self-administration.

1. Addictive substances such as cocaine and heroin characteristically
support rapid acquisition of intravenous self-administration in a large
percentage of the experimental animals tested. By contrast, few laboratories
have reported successful nicotine self-administration. There have been
numerous published failures with nicotine, and yet the scientific literature
is always strongly biased in favor of positive findings.

2. Special testing conditions are not necessary to demonstrate the potent
reinforcing effects of true addictive substances such as cocaine and heroin.
By contrast, special testing conditions are necessary to demonstrate nicotine
self-administration.

(1) most studies house the monkeys in social isolation, and
(2) restraint chairs are frequently used to immobilize the subjects.
C. Most studies reporting nicotine self-administration have not used experimentally
naive subjects:
(1) some subjects have previous training with prototypic addictive
drugs, while
(2) other subjects have previous training with a food reinforcer.
3. Self-administration behavior of prototypic addictive drugs is maintained
with a variety of reinforcement schedules.
A. Continuous reinforcement schedules (CRF) are always effective with
such addictive drugs; and

C. Again, nicotine is different. Positive findings with nicotine are
reported with only a few reinforcement schedules.

(1) Indeed, CRF schedules have been consistently reported not
to work with nicotine. (Yet this reinforcement schedule should be the most
effective in establishing behavior.)
(2) And some of the reinforcement schedules that have been reported
to work with nicotine are also effective in maintaining responding with
painful electric shock.
4. Response patterns for a true addictive substance such as cocaine or
heroin are predictable from its pharmacological activity.
A. A wide range of substance doses is usually effective with such
drugs. With nicotine, only a very narrow dose range is effective.

B. With addictive substances, behavioral compensation occurs following
changes in unit dose (i.e., the amount of drug given with each injection).
No such apparent regulation of intake has generally been seen with nicotine.

D. By contrast, the effects of specific receptor-antagonist pretreatments
in reported nicotine self-administration are anomalous showing a failure
to observe:

(1) increased nicotine intake with low antagonist doses or
(2) extinction-like response patterns with higher antagonist doses.
5. A number of experimental control procedures have been used to insure
the validity of the main conclusions from studies of prototypic addictive
drugs such as cocaine and heroin; these procedures are designed to show
that the substance is serving as a reinforcer. By contrast, control procedures
are generally inadequate to show that responding is due to nicotine reinforcement.
A. Most studies neglect the effect of mild stimulants on low-rate
operant behavior; and

B. The two-lever choice test does not eliminate treatmentxstimulus-presentation interactions--yoked
control procedures need to be tested with nicotine to eliminate this possible
experimental artifact.

6. Finally, intravenous self-administration of prototypic addictive substances
is uniformly demonstrable across a high proportion of the experimental
subjects tested, a wide range of mammalian species (e.g., rodents, monkeys,
humans), and a number of different laboratories and scientific investigators.
By contrast, positive findings with nicotine are reported from only a few
laboratories.
A. Nicotine self-administration appears to be very sensitive to minor
procedural differences; and

B. The findings are somewhat controversial among drug reinforcement
specialists.

Conclusions from the Nicotine Self-Administration Literature

The interpretation of the data is largely biased by the prior assumption
that nicotine is addictive. If that assumption is suspended, however, it
is clear the animal studies are inconclusive or even argue against the
"nicotine addiction" hypothesis.

1. Nicotine is, at best, an equivocal reinforcer in intravenous self-administration
tests. Few investigators have obtained positive findings under any testing
conditions. If we were to accept the reports of nicotine self-administration
as valid, then:
A. nicotine is a reinforcer only under very limited testing conditions,
and

B. nicotine reinforcement appears much less potent than reinforcement
from natural rewards (e.g., food, water) which is considerably less potent
than reinforcement from prototypic addictive drugs.

2. Nicotine clearly does not have the profile shared by prototypic addictive
drugs.

3. For a drug (or any substance) to be addictive, it must serve as a
reinforcer. But simply serving as a reinforcer does not constitute addiction
unless we wish to classify all behavior as addictive. Motivational strength
must be considered when evaluating the addiction liability of a substance.
This will be reflected by four variables: the speed of acquiring the response,
the resistance to extinction, the work output the subject will generate
to obtain the reward, and the amount of aversive stimulation the subject
will tolerate to obtain the reward. These variables must be considered
if the intravenous self-administration of a substance by laboratory animals
is to be used to decide addiction liability.

Nicotine & Brain Reward Mechanisms

The brain has specialized pathways that mediate motivation and reward.
One of the systems studied most extensively is the mesolimbic dopamine
system. This "reward" pathway appears to be involved in the reinforcing
effects of a number of distinctively different rewards, including natural
rewards such as food, sex, and maternal behavior. This pathway may also
play a critical role in the genesis of drug addiction. Prototypic addictive
drugs (e.g., cocaine, heroin) activate this pathway, as do other nonaddictive
substances. The fact that two distinctively different pharmacological drug
classes (i.e., psychomotor stimulants and opiates) may derive a major part
of their reinforcing effects by activating a common reward substrate suggests
a biological mechanism for a unifying theory of addiction. It is particularly
enticing to speculate that other drugs with a clear addiction liability
(e.g., barbiturates, ethanol) may also derive a major part of their reinforcing
effects by activating this substrate. As with any theoretical model, the
more behaviors the model can explain the more comprehensive the model.
This has prompted speculation and study of the effects of other rewards
on mesolimbic dopamine activity.

The fact that a substance can activate brain reward mechanisms does
not suggest that the substance is addictive. Natural motivators also exert
their influence on behavior by activating brain reward mechanisms. The
pleasure experienced from cigarette smoking may involve specific brain
pathways, but this is not fundamentally different than activation of these
same pathways through sensory stimulation such as sweet taste or sexual
gratification. It is simply a question of which neural element initiates
the reward signal: peripheral sensory receptors or central neural components.
The control addictive drugs exert over behavior is distinctively different
from the modest effect produced by "life's little pleasures."

The exact role of brain reward systems in drug addiction is unclear.
It is probably the case that activation of reward processes is necessary
but not sufficient to produce an addiction. Reinforcement theory
can be used to describe the relationship between the behavior and the drug
presentation, but the mechanism appears more complex than simple activation
of brain reward systems.

The "Voluntary" Nature of Cigarette Smoking

The issue of whether to regulate nicotine seems to focus on whether
cigarette smoking is considered a voluntary act or whether it is the consequence
of an addiction to nicotine and therefore not under the smoker's control.
For a behavioral scientist, it is very difficult to reconcile the notion
of "voluntary" behavior with the doctrine of empirical determinism. Cause-and-effect
figures predominantly in experimental psychology. Behavior is viewed as
the inevitable consequence of antecedent conditions, and the notion of
free will is usually excluded from scientific consideration. However, upon
pondering the question further it is possible to develop an operational
definition of "voluntary" that satisfies the general sense conveyed by
the layman's use of this term.

Voluntary behavior is considered behavior of choice. In more scientific
terms, the behavior might be considered under the normal control of multiple
factors and competing response tendencies. A number of motivations normally
compete for the individual's attention. The desire to eat, to sleep, and
to have sex may all motivate the individual at the same time. Which behavior
predominates is the result of a complex interaction among the relative
strengths of the motives, prevailing stimuli, and current physiological
conditions. The normal interplay among various motives with no one motivation
dominating the individual's behavior gives rise to a sense of self-control.

In the case of addiction, behavior is described as involuntary (i.e.,
loss of self-control). The motivational properties of the drug override
the normal influence of natural rewards. This feature is more formally
termed motivational toxicity. This is probably the result of the
intense motivational strength of the drug reward and the diminished rewarding
impact of other reinforcers.

The cigarette smoker experiences no such blunting of life's other rewards
and pleasures. Indeed, smoking is frequently reported to enhance
other pleasures. There is no extreme focusing of motivational priorities
nor any disruption of the ability of other rewards to engage behavior.
In short, there is no motivational toxicity displayed by cigarette smokers.
Furthermore, behavior is still under the control of other motives and hence
smoking must be considered "voluntary" behavior.

Challenges to the "Nicotine Addiction" Hypothesis

There are a number of challenges to the "nicotine addiction" hypothesis.
Some of them concern the empirical studies and others are conceptual. Some
of the scientific data have been accepted as fact without seriously entertaining
alternative explanations. Hasty conclusions have been drawn from these
data, frequently without considering elementary principles of experimental
psychology and behavioral neurobiology.

Nicotine has only equivocal reinforcing effects in laboratory animals.
These effects generally have not been replicated across laboratories, and
the special testing conditions apparently necessary to demonstrate nicotine
reinforcement have not been identified. Even if nicotine can be shown to
reliably serve as a reinforcer, reinforcement from a substance is not equivalent
to addiction. Otherwise, all behavior must be labeled addictive.

Reinforcement appears necessary to establish addiction, but reinforcement
is not sufficient to produce an addiction. Most reinforcers are not
"addictive." Drug addiction probably involves mechanisms other than simple
reinforcement. Newer theories of addiction focus on neuroadaptive changes
in brain reward mechanisms, and prototypic addictive drugs (e.g., cocaine,
heroin) have been reported to produce changes in these brain systems.

Nicotine administration does not produce the primary characteristics
of addiction. Specifically, neither extreme motivational potency nor
motivational toxicity are associated with tobacco use. These effects are
the hallmarks of addiction, and these effects are not typically associated
with tobacco use. Nicotine does not propel itself to the top of the individual's
motivations nor does it impair the ability of natural rewards to motivate
behavior.

There is considerable confusion among the nonspecialists regarding the
significance of activating brain reward pathways. Natural rewards activate
these pathways and this process is part of the normal generation of behavior.
Activation of brain reward mechanisms is not equivalent to addiction.
Nicotine may activate brain reward mechanisms (e.g., produce a mildly pleasurable
sensation), but so do all rewards!

For all these reasons, the data do not support the assertion that
nicotine is addictive. Considerably more research needs to address
the complex motivations for smoking behavior.